This is a new Program Project to establish an interdisciplinary research program to determine the role of the oropharyngeal environment in the transmission and pathogenesis of the Kaposi's sarcoma-associated herpesvirus (KSHV). Kaposi's sarcoma (KS) was recognized as one of the first clinical manifestations of HIV, and today remains the most common AIDS-associated malignancy. KSHV is endemic in Sub-Saharan Africa, with extremely high infection rates in children, adolescents and adults. Compounded with the high rate of HIV and AIDS in this geographical area, pediatric and adult KS are some of the most common malignancies, with the highest fatality rates. The Project leaders have played key roles in the initial discovery and characterization of KSHV, and in the role of the oral environment in the acquisition and transmission of the virus. Furthermore, they have also been at the forefront of research on the role of the immune response in regulating KSHV infection. Four interrelated research projects with associated administrative, cell culture and clinical cores are proposed. These projects collectively address fundamental questions regarding how KSHV infection leads to KS. Project 1(PI,T. Rose) will study the role of cell-cell transmission of KSHV during acquisition in oral tissues and dissemination to peripheral tissues. Project 2 (PI, J. Vieira) will investigate the reactivation of latently-infected cells to begin producing infectious virus. Project 3 (PI. M. LagunofO will examine the process by which KSHV infection of cells causes them to differentiate into KS tumor cells. Project 4 (Co-Pls, S. Gantt/S. Barcy) seeks to identify which immune responses are responsible for controlling KSHV infection, and how HIV impairs these responses. Finally, each of these Projects will explore the clinical relevance of their findings in natural human KSHV infection, by collaborating with the Uganda Program on Cancer and Infectious Disease (UPCID) to study infection in communities with the highest known incidence of KS. The interrelated nature of these four projects, the technological synergism and the existing research collaborations provide an exceptionally strong basis for this project, which could lead to new therapeutic treatments for KSHV infection and KS.